Process for the preparation of a pyrazolo[4,3-d]pyrimidine derivative

ABSTRACT

The invention relates to a process for the preparation of [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy]acetic acid and intermediates thereof.

[0001] The invention relates to a process for the preparation of[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy]aceticacid.

[0002] This substance specifically inhibits cGMP phosphodiesterase (PDEV).

[0003] Compounds of the formula I

[0004] in which

[0005] R¹ and R² are each, independently of one another, H, A, OH, OA orHaI,

[0006] R¹ and R² together are alternatively alkylene having 3-5 carbonatoms, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —O—CH₂—O— or —O—CH₂—CH₂—O—,

[0007] R³ and R⁴ are each, independently of one another, H or A,

[0008] X is R⁵, R⁶ or R⁷, each of which is monosubstituted by R⁸,

[0009] R⁵ is linear or branched alkylene having 1-10 carbon atoms, inwhich one or two CH₂ groups may be replaced by —CH═CH— groups, O, S orSO,

[0010] R⁶ is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,

[0011] R⁷ is phenyl or phenylmethyl,

[0012] R⁸ is COOH, COOA, CONH₂, CONHA, CON(A)₂ or CN,

[0013] A is alkyl having from 1 to 6 carbon atoms, and

[0014] Hal is F, Cl, Br or I,

[0015] and physiologically acceptable salts and solvates thereof areknown.

[0016] Other pyrimidine derivatives are known, for example, from EP 201188 or WO 93/06104.

[0017] The compounds of the formula I and their salts have very valuablepharmacological properties and are well tolerated.

[0018] In particular, they exhibit specific inhibition of cGMPphosphodiesterase (PDE V).

[0019] Quinazolines having a cGMP phosphodiesterase-inhibiting activityare described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid.37, 2106 (1994).

[0020] The biological activity of the compounds of the formula I can bedetermined by methods as described, for example, in WO 93/06104.

[0021] The affinity of the compounds according to the invention for cGMPand cAMP phosphodiesterase is determined by measuring their IC₅₀ values(concentration of the inhibitor needed to achieve 50% inhibition of theenzyme activity).

[0022] The determinations can be carried out using enzymes isolated byknown methods (for example W. J. Thompson et al., Biochem. 1971, 10,311). The experiments can be carried out using a modified batch methodof W. J. Thompson and M. M. Appleman (Biochem. 1979, 18, 5228).

[0023] The compounds are therefore suitable for the treatment ofillnesses of the cardiovascular system, in particular cardiacinsufficiency, and for the treatment and/or therapy of potency disorders(erectile dysfunction).

[0024] The use of substituted pyrazolopyrimidinones for the treatment ofimpotence is described, for example, in WO 94/28902.

[0025] The compounds are effective as inhibitors ofphenylephrine-induced contractions in corpus cavernosum preparations ofrabbits. This biological action can be demonstrated, for example, by themethod described by F. Holmquist et al. in J. Urol., 150, 1310-1315(1993).

[0026] The inhibition of the contraction demonstrates the effectivenessof the compounds according to the invention for the therapy and/ortreatment of potency disorders.

[0027] The compounds of the formula I can be employed as medicamentactive ingredients in human and veterinary medicine. They canfurthermore be employed as intermediates in the preparation of furthermedicament active ingredients.

[0028][7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid has proven to be a highly suitable and highly effective substance.This substance has not only a very good action in the treatment oferectile dysfunction, but can also advantageously be employed in thetreatment of pulmonary hypertension.

[0029] Since this substance is very highly promising, its preparation isof extremely high interest. The preparation of this class of substancesis described, for example, in EP 463756 and EP 526004. Processes forsimilar intermediates are disclosed, for example, in EP 819678.

[0030] There is therefore considerable interest in finding an improvedprocess for the preparation of[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid.

[0031] The object of the present invention was therefore to find a noveland effective synthesis variant for the said PDE V inhibitor.

[0032] The invention therefore relates to a process for the preparationof[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid

[0033] where

[0034] a) 1-methyl-3-propyl-4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”)is reacted with diglycolic anhydride to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)methoxy]aceticacid (“Z7”) or

[0035] a′) “Z6” is reacted with a compound of the formula (“Z7B”)

L-CO—CH₂—O—CH₂—COOA  “Z7B”

[0036]  where L is Cl, Br, OH, SCH₃ or a reactive esterified OH group,and

[0037] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0038]  or benzyl,

[0039]  to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-methoxy]-aceticacid A ester (“Z7B”),

[0040]  where

[0041] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0042]  or benzyl,

[0043]  subsequently

[0044] b) “Z7” or “Z7B” is converted into(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy)aceticacid (“Z8”) by cyclisation, then

[0045] c) “Z8” is converted into(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy)aceticacid A ester (“Z9”),

[0046]  where

[0047] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0048]  or benzyl,

[0049]  subsequently

[0050] d) “Z9” is converted into(7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)aceticacid A ester (“Z10”),

[0051]  where

[0052] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0053]  or benzyl,

[0054]  by oxygen-chlorine exchange,

[0055]  subsequently

[0056] e) “Z10” is reacted with 3-chloro-4-methoxybenzylamine to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid A ester (“Z 11”),

[0057]  where

[0058] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0059]  or benzyl,

[0060]  and finally

[0061] f) “Z 11” is hydrolysed to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid (“Z12”).

[0062] The starting materials for the preparation of[7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy]aceticacid are, in addition, prepared by methods known per se, as described inthe literature (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditionswhich are known and suitable for the said reactions. Use can also bemade here of variants which are known per se, but are not mentioned herein greater detail.

[0063] The aminoamide “Z6” is known from the literature.

[0064] The reaction of “Z6” with diglycolic anhydride to give “Z7” iscarried out in the presence or absence of an inert solvent attemperatures between about −20 and about 1500, preferably between 20 and100°. The yields are about 90%.

[0065] The reaction of “Z6” with a compound of the formula “Z7B” islikewise carried out in the presence or absence of an inert solvent attemperatures between about −20 and about 150°, preferably between 20 and100°. If L is a reactive esterified OH group, this is preferablyalkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy)or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy, furthermore also 2-naphthalenesulfonyloxy).

[0066] Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbontetrachloride, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, suchas acetone or butanone; amides, such as acetamide, dimethylacetamide,N-methylpyrrolidone or dimethylformamide (DMF); nitriles, such asacetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitrocompounds, such as nitromethane or nitrobenzene; esters, such as ethylacetate, or mixtures of the said solvents.

[0067] The conversion of “Z7” into “Z8” is carried out in an aqueoussolution of an alkali metal hydroxide or alkaline earth metal hydroxideat temperatures between about −20 and about 150°, preferably between 20and 120°, very particularly preferably between 80° and 110°. Thecyclisation is preferably carried out in aqueous NaOH or KOH solution.The yields are about 93%.

[0068] The esterification of “Z8” to “Z9” is carried out by knownmethods at temperatures between about −20 and about 150°, preferablybetween 20 and 100°, using the corresponding alcohols. The yields areabout 95%.

[0069] The conversion of “Z9” into “Z10” is preferably carried out usingphosphorus oxychloride (analogously to Houben Weyl E9b/2) with additionof an organic base, such as N-ethyldiisopropylamine, triethylamine,dimethylamine, pyridine or quinoline, at temperatures between about −20°and about 100°, preferably between 0° and 60°.

[0070] It is also possible to add an inert solvent, as indicated above.The yields are about 90%.

[0071] The reaction of “Z10” with 3-chloro-4-methoxybenzylamine to give“Z 11” is carried out in the presence or absence of an inert solvent attemperatures between about −20 and about 150°, preferably between 20 and100°.

[0072] The addition of an acid-binding agent, for example an alkali oralkaline earth metal hydroxide, carbonate or bicarbonate, or of anothersalt of a weak acid of the alkali or alkaline earth metals, preferablyof potassium, sodium or calcium, or the addition of an organic base,such as triethylamine, dimethylamine, pyridine or quinoline, or of anexcess of the amine component may be favourable. Suitable inert solventsare those mentioned above.

[0073] The hydrolysis of “Z11” to “Z12” can be carried out, for example,using NaOH or KOH in water, water/THF or water/dioxane at temperaturesbetween 0 and 100°.

[0074] “Z12” can be converted into the associated acid-addition saltusing a base, for example by reaction of equivalent amounts of the acidand the base in an inert solvent, such as ethanol, followed byevaporation. Suitable bases for this reaction are, in particular, thosewhich give physiologically acceptable salts.

[0075] Thus, the acid of the formula I can be converted using a base(for example sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate) into the corresponding metal salt, in particularalkali metal salt or alkaline earth metal salt, or into thecorresponding ammonium salt. Organic bases which give physiologicallyacceptable salts, such as, for example, ethanolamine, are alsoparticularly suitable for this reaction.

[0076] The invention relates, in particular, to a process for thepreparation of[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid

[0077] where

[0078] a) diethyl oxalate is reacted with methyl propyl ketone to giveethyl 2,4-dioxoheptanoate (“Z1”),

[0079]  subsequently

[0080] b) “Z1” is converted into 3-propyl-5-ethoxycarbonyl-1H-pyrazole(“Z2”),

[0081]  then

[0082] c) “Z2” is converted into 1-methyl-3-propyl-5-carboxy-1H-pyrazole(“Z3”) by methylation and hydrolysis,

[0083]  subsequently

[0084] d) 1-methyl-3-propyl-4-nitro-5-carboxy-1H-pyrazole (“Z4”) isobtained from “Z3” by nitration,

[0085]  then

[0086] e) “Z4” is converted into the carboxamide1-methyl-3-propyl-4-nitro-5-aminocarbonyl-1H-pyrazole (“Z5”),

[0087]  subsequently

[0088] f) “Z5” is converted into1-methyl-3-propyl-4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”) byreduction,

[0089]  then

[0090] g) 1-methyl-3-propyl-4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”)is reacted with diglycolic anhydride to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)methoxy]aceticacid (“Z7”) or

[0091] g′) “Z6” is reacted with a compound of the formula (“Z7B”)

L-CO—CH₂—O—CH₂—COOA  “Z7B”

[0092]  where L is Cl, Br, OH, SCH₃ or a reactive esterified OH group,and

[0093] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl,

[0094]  to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol4-ylcarbamoyl)-methoxy]aceticacid A ester (“Z7B”),

[0095]  where

[0096] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl,

[0097]  subsequently

[0098] h) “Z7” is converted into(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy)aceticacid (“Z8”) by cyclisation,

[0099]  then

[0100] i) “Z8” is converted into(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy)aceticacid A ester (“Z9”),

[0101]  where

[0102] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl,

[0103]  subsequently

[0104] j) “Z9” is converted into(7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)aceticacid A ester (“Z10”),

[0105]  where

[0106] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl,

[0107]  by oxygen-chlorine exchange,

[0108]  subsequently

[0109] k) “Z10” is reacted with 3-chloro-4-methoxybenzylamine to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid A ester (“Z11”),

[0110]  where

[0111] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl,

[0112]  and finally

[0113] l) “Z11” is hydrolysed to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid (“Z12”).

[0114] Compounds “Z1” to “Z6” are known from the literature.

[0115] The invention furthermore relates to the novel intermediates

[0116] a)[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol4-ylcarbamoyl)-methoxy]aceticacid;

[0117] b)[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol4-ylcarbamoyl)methoxy]aceticacid A ester,

[0118]  where

[0119] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0120]  or benzyl;

[0121] c)(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)aceticacid;

[0122] d)(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)aceticacid A ester,

[0123]  where

[0124] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0125]  or benzyl;

[0126] e)(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)aceticacid A ester,

[0127]  where

[0128] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0129]  or benzyl;

[0130] f)[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid A ester,

[0131]  where

[0132] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms

[0133]  or benzyl;

[0134] g)[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid,

[0135] and salts and solvates thereof.

[0136] The starting materials for the preparation of[7-(3-chloro-4-methoxy-benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy]aceticacid are, in addition, prepared by methods known per se, as described inthe literature (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditionswhich are known and suitable for the said reactions. Use can also bemade here of variants which are known per se, but are not mentioned herein greater detail.

[0137] The term “solvates of the compounds of the formula I” is taken tomean adductions of inert solvent molecules onto the compounds of theformula I which form owing to their mutual attractive force. Solvatesare, for example, mono- or dihydrates or alcoholates.

[0138] A is alkyl having 1-6 carbon atoms.

[0139] In the above compounds, alkyl is preferably unbranched and has 1,2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl,furthermore preferably isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.

[0140] Above and below, all temperatures are given in ° C. In thefollowing examples, “conventional work-up” means that water is added ifnecessary, the pH is adjusted, if necessary, to between 2 and 10,depending on the constitution of the end product, the mixture isextracted with ethyl acetate or dichloromethane, the phases areseparated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallisation.

[0141] Mass spectrometry (MS): El (electron impact ionisation) M⁺FAB(fast atom bombardment) (M+H)⁺

EXAMPLE 1

[0142] 1.1 13.5 g of diglycolic anhydride are added at 15° to a solutionof 20.5 g of 1-methyl-3-propyl4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”)in 400 ml of dichloromethane, and the mixture is stirred for a further 1hour. The mixture is subjected to conventional work-up, giving 32.5 g of[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol4-ylcarbamoyl)methoxy]-aceticacid (“Z7”).

[0143] 1.2 A solution of 10.0 g of “Z7” and 3.9 g of NaOH in 217 ml ofwater is heated at 95° for 1.5 hours. The mixture is cooled andsubjected to conventional work-up, giving 9 g of(7-oxo-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)aceticacid (“Z8”).

[0144] 1.3 0.3 ml of sulfuric acid (95-97%) is added to a solution of7.0 g of “Z8” in 80 ml of ethanol, and the mixture is refluxed for 2hours. The solvent is removed, and the mixture is subjected toconventional work-up, giving 7 g of ethyl(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy)acetate.

[0145] 1.4 110 ml of phosphoryl chloride are added to 14.8 g of ethyl(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy)acetate,then 9.5 ml of N-ethyidiisopropylamine are added at 100 with stirring,and the mixture is stirred at 50° for a further 3 hours.

[0146] The solvents are removed, then ice-water is added, and themixture is subjected to conventional work-up, giving 14 g of ethyl(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy)acetateas an oil.

[0147] 1.5a 3 g of ethyl(7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)acetateand 1.9 g of 3-chloro-4-methoxy-benzylamine in 50 ml ofdimethylformamide (DMF) are stirred at 60° for 12 hours in the presenceof potassium carbonate. After filtration, the solvent is removed, andthe mixture is subjected to conventional work-up, giving 4.6 g of ethyl[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetate.

[0148] or 1.5b

[0149] A mixture of 1.8 g of ethyl(7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)acetateand 1.5 g of 3-chloro-4-methoxy-benzylamine in 20 ml ofN-methylpyrrolidone is warmed at 1100 for 4 hours. After cooling, themixture is subjected to conventional work-up, giving 2.2 g of ethyl[7-(3-chloro-4-methoxybenzylamino-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetate.

[0150] 1.6 4.3 g of ethyl[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetateare dissolved in 30 ml of tetrahydrofuran (THF), 10 ml of 10% NaOH areadded, and the mixture is stirred at 60° for 8 hours. After 10% HCl hasbeen added, the deposited crystals are separated off and recrystallisedfrom methanol, giving 3.7 g of[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid.

[0151] Evaporation with the equivalent amount of ethanolamine inmethanol gives[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid, ethanolamine salt, m.p. 138°.

1. Process for the preparation of[7-(3-chloro-4-methoxybenzyl-amino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid

where a) 1-methyl-3-propyl4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”) isreacted with diglycolic anhydride to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)methoxy]aceticacid (“Z7”) or a′) “Z6” is reacted with a compound of the formula(“Z7B”) L-CO—CH₂—O—CH₂—COOA  “Z7B”  where L is Cl, Br, OH, SCH₃ or areactive esterified OH group, and A is alkyl having 1, 2, 3, 4, 5 or 6carbon atoms  or benzyl,  to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-methoxy]aceticacid A ester (“Z7B”),  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms  or benzyl,  subsequently b) “Z7” or “Z7B” is converted into(7-oxo-1-methyl-3-propyl-1 H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy)aceticacid (“Z8”) by cyclisation, then c) “Z8” is converted into(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy)aceticacid A ester (“Z9”),  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms  or benzyl,  subsequently d) “Z9” is converted into(7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)aceticacid A ester (“Z10”),  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms  or benzyl,  by oxygen-chlorine exchange,  subsequently e) “Z10”is reacted with 3-chloro-4-methoxybenzylamine to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid A ester (“Z 11”),  where A is alkyl having 1, 2, 3, 4, 5 or 6carbon atoms  or benzyl,  and finally f) “Z11” is hydrolysed to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid (“Z12”).
 2. Process for the preparation of[7-(3-chloro-4-methoxybenzyl-amino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetic acid

where a) diethyl oxalate is reacted with methyl propyl ketone to giveethyl 2,4-dioxoheptanoate (“Z1”),  subsequently b) “Z1” is convertedinto 3-propyl-5-ethoxycarbonyl-1H-pyrazole (“Z2”),  then c) “Z2” isconverted into 1-methyl-3-propyl-5-carboxy-1H-pyrazole (“Z3”) bymethylation and hydrolysis,  subsequently d)1-methyl-3-propyl-4-nitro-5-carboxy-1H-pyrazole (“Z4”) is obtained from“Z3” by nitration,  then e) “Z4” is converted into the carboxamide1-methyl-3-propyl4-nitro-5-aminocarbonyl-1H-pyrazole (“Z5”), subsequently f) “Z5” is converted into1-methyl-3-propyl-4-amino-5-aminocarbonyl-1H-pyrazole (“Z6”) byreduction,  then g) 1-methyl-3-propyl4-amino-5-aminocarbonyl-1H-pyrazole(“Z6”) is reacted with diglycolic anhydride to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol4-ylcarbamoyl)methoxy]aceticacid (“Z7”) or g′) “Z6” is reacted with a compound of the formula(“Z7B”) L-CO—CH₂—O—CH₂—COOA  “Z7B”  where L is Cl, Br, OH, SCH₃ or areactive esterified OH group, and A is alkyl having 1, 2, 3, 4, 5 or 6carbon atoms  or benzyl,  to give[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-methoxy]aceticacid A ester (“Z7B”),  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms  or benzyl,  subsequently h) “Z7” is converted into(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy)aceticacid (“Z8”) by cyclisation,  then i) “Z8” is converted into(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy)aceticacid A ester (“Z9”),  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms  or benzyl,  subsequently j) “Z9” is converted into(7-chloro-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-ylmethoxy)aceticacid A ester (“Z10”),  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms  or benzyl,  by oxygen-chlorine exchange,  subsequently k) “Z10”is reacted with 3-chloro-4-methoxybenzylamine to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-ylmethoxy]aceticacid A ester (“Z11”),  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms  or benzyl,  and finally l) “Z11” is hydrolysed to give[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid (“Z12”).
 3. Compounds selected from the group consisting of a)[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-methoxy]aceticacid; b)[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-methoxy]aceticacid A ester,  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl; c)(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)aceticacid; d)(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)aceticacid A ester,  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl; e)(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)aceticacid A ester,  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl; f)[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid A ester,  where A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or benzyl; g)[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]aceticacid, and salts and solvates thereof.
 4. Compounds according to claim 3,selected from the group consisting of a) ethyl[(5-aminocarbonyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)methoxy]acetate;b) ethyl(7-oxo-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)acetate;c) ethyl(7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl-methoxy)acetate;d) ethyl[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetate;and salts and solvates thereof.